The discovery of the activating V617F mutation in Janus kinase 2 (JAK2) in the majority of patients with the classic Philadelphia chromosome-negative (Ph−) myeloproliferative neoplasms (MPN) provided a strong impetus for the development of pharmacologic inhibitors of JAK2, culminating in the regulatory approval of the JAK1/2 inhibitor, ruxolitinib, for patients with myelofibrosis (MF) in 2011 and hydroxyurea (HU)-resistant/intolerant polycythemia vera (PV) in 2014. The activity of ruxolitinib in patients with MF without regard to JAK2 mutation status was an important observation that was vindicated by the finding of universal activation of the JAK-signal transducer and activator of transcription (STAT) pathway in MPNs.
However, because JAK2 signaling is not suppressed long term and molecular remission is not observed in patients treated with JAK2 inhibitors, there is a need for new therapies to improve patient outcome. This application is directed to this need and others.